Skeletal muscle plays key roles in glucose and lipid homeostasis, and contributes to whole body energy expenditure. Poor physical fitness and inactivity are risk factors for developing type 2 diabetes, a disease reaching epidemic proportions. Conversely, physical activity is effective in improving metabolic health, by enhancing insulin sensitivity and improving lipid parameters. Interestingly, both the capacity for exercise, and the metabolic benefits and responses to exercise, vary greatly among individuals and are decreased in some disease states. Thus, elucidating the mechanisms that determine muscle function and fitness (and thereby enable exercise), and mediate exercise-induced skeletal muscle responses, is important for finding new ways to target muscle and improve metabolic health. The family of estrogen-related receptors (ERR?, ERR? and ERR?) regulates oxidative metabolism and other pathways important for energy homeostasis. As members of the nuclear receptor family, ERRs have pockets that accommodate synthetic ligands and can thus be targeted therapeutically. Our preliminary data show that all three members of the family are expressed in skeletal muscle and activated by exercise signals. We also show that ERRs collectively determine the expression of genes important for metabolic and contractile properties of skeletal muscle. In the proposed work, we will use mice lacking ERRs specifically in skeletal muscle, to define the cellular and physiologic functions of ERR?, ERR? and ERR? in skeletal muscle, at the basal state and in adaptive responses to endurance exercise. We will also use gain- and loss-of- function approaches in vivo to delineate the physiological function and mechanism of action of Perm1, a novel ERR downstream effector that we recently identified as regulating skeletal muscle oxidative capacity. Overall, we expect to provide novel insights into regulatory mechanisms that enable and shape skeletal muscle adaptive responses to endurance exercise, and to inform on pathways relevant to disease states where oxidative metabolism and muscle function are compromised, such as insulin resistance and type 2 diabetes, disease-associated or injury-caused muscle atrophies, and age-related muscle degeneration. Our findings will be important for guiding future efforts to use ERR?/? agonists o enhance muscle function and/or benefits from exercise.